Drug addiction has been considered a chronic disease and a risk factor for many other diseases and disorders. To better treat addiction and prevent future abuse of illicit drugs, it is essential to understand the mechanisms underlying addictive behaviors. Clinical and animal studies have established that the metabolic status contributes to the determination of reward threshold in humans and animals. Food restriction increases the sensitivity to drugs of abuse, while over-nutrition decreases the sensitivity to drugs. However, it is still elusive how the brain circuitry regulating the metabolic status interacts with the reward circuitry. The lateral hypothalamus (LH), a central hub integrating a wide range of inputs from various brain regions encoding metabolic, behavioral and environmental cues, is a critical brain area to regulate both energy homeostasis and food/drug reward. Particularly, a selective group of neurons exclusively synthesizing the neuropeptide hypocretin (Hcrt, also called orexin) affect food intake and play a prominent role in food award and drug addiction. Currently it is not entirely clear what role the Hcrt system plays in the hierarchy of circuitry responsible for food reward and drug addiction. Recent studies by others and us indicate that the Hcrt system undergoes experience-dependent synaptic plasticity in animals exposed to cocaine, which leads to our overall hypothesis that the expression of experience-dependent synaptic plasticity in Hcrt cells contributes to the development of addictive behaviors in animals. If this is true, the ability to establish synaptic plasticity in Hcrt neurons may contribute to the susceptibility of animals to addictive behaviors. Based on our previous studies, we hypothesize that the metabolic status of animals may contribute to determination of sensitivity to cocaine through modulating synaptic plasticity in Hcrt neurons. In this R21 application we will begin to address this hypothesis by determining whether either diet-induced obesity (DIO) or chronic calorie restriction (CR) alters the ability of cocaine to trigger plasticity in the Hcrt system with molecular (Hcrt-IRES-Cre mice and DREADDs), cellular (electrophysiological and EM studies) and behavioral (cocaine conditioned place preference) approaches. Two specific aims are: 1) To determine whether DIO induces adaptation in Hcrt neurons, which impedes the expression of activity (or experience)-dependent synaptic plasticity. 2) To determine whether chronic CR induces adaptation in Hcrt neurons, which facilitates the expression of activity (or experience)-dependent synaptic plasticity. Following completion of these important proof-of-concept studies, we will conduct a more comprehensive study to determine how molecular and cellular signaling pathways in Hcrt neurons contribute to the development of addictive behaviors in animals under different metabolic status. Our long-term goal is to bridge the knowledge gap in our current understanding of addiction and to bridge the gap between clinical studies and basic research on the role of the Hcrt system in addictive behaviors, an area of study that has not been well explored thus far.